Systems and methods for delivery of therapeutic agents

ABSTRACT

An iontophoresis system includes a preloaded reservoir containing one or more doses of a therapeutic agent. As a result, the therapeutic agent does not have to be loaded into the reservoir prior to use. In such a system, the preloaded reservoir is generally disposable. Various components of the iontophoresis system can be combined with the reservoir in a disposable cartridge that is selectively connectable to other, reusable components of the iontophoresis system. In addition, the entire iontophoresis system can be formed from one or more disposable, one-time-use modules.

FIELD

The present disclosure generally relates to systems and methods fordelivering therapeutic agents to a body portion of a patient and, morespecifically, to methods and systems using electrical and/or acousticenergy to deliver therapeutic agents.

BACKGROUND

Various techniques can be used to cause a therapeutic agent to penetratetissue. For example, injections are commonly used to deliver atherapeutic agent to a location in or below the skin. Other techniquessuch as iontophoresis and sonophoresis can also be used and may be lessinvasive and/or painful. Iontophoresis uses an electrical field to drivean ionic therapeutic agent into target tissue. Sonophoresis usesacoustic energy to increase the permeability of tissue and drive atherapeutic agent that is suspended in a glycerin coupling gel into thetarget tissue. Each of these techniques is most frequently used for thetransdermal administration of topical therapeutic agents. Althoughiontophoresis and sonophoresis have certain benefits over injections,such as being less invasive and painful, they have not been widelyadopted. One primary limitation of these techniques is the inability toensure accurate dosing. With iontophoresis, a user must fill a reservoirwith the required amount of therapeutic agent prior to use. Moreover,once the device is filled, conventional iontophoresis systems lack thecapability to accurately determine how much of the therapeutic agent isbeing absorbed. Furthermore, certain tissues can lack sufficientpermeability to adequately administer a complete dose. It is likewisedifficult to accurately administer a dose of therapeutic agent usingsonophoresis. A therapeutic agent is suspended in acoustic coupling gel,which cannot be fully absorbed into the skin. The residual coupling gelleft on the skin retains an unknown quantity of suspended therapeuticagent, which makes it difficult to determine how much of the therapeuticagent is properly administered.

SUMMARY

In one aspect, an iontophoresis system includes a preloaded reservoircontaining one or more doses of a therapeutic agent. As a result, thetherapeutic agent does not have to be loaded into the reservoir prior touse. In such a system, the preloaded reservoir is generally disposable.Various components of the iontophoresis system can be combined with thereservoir in a disposable cartridge that is selectively connectable toother, reusable components of the iontophoresis system. In addition, theentire iontophoresis system can be formed from one or more disposable,one-time-use modules.

In another aspect, an iontophoresis system is configured so that anactive electrode and an indifferent electrode generally oppose oneanother when the electrodes are mounted on the body of the patient. Theindifferent electrode is thought to aid the active electrode in drivingthe charged therapeutic agent into the body portion to improvepenetration.

In another aspect, an iontophoresis system includes active andindifferent electrodes, as well as an auxiliary device, configured to beselectively coupled to the body portion of a patient. In certainembodiments, the auxiliary device is thought to enhance penetration of atherapeutic agent into the body portion of the patient, as compared withusing the active and indifferent electrodes alone. Examples of suitableauxiliary devices include a heater, a chiller, an acoustic energygenerator, an abrader, a vibrator, etc. An auxiliary device and theactive and indifferent electrodes can be operated by an automatedcontrol system that automatically controls the apparatuses to improvepenetration and/or another therapeutic variable.

In another aspect, an iontophoresis system includes one or more sensorsconfigured to detect one or more conditions related to the quantity of atherapeutic agent that is effectively absorbed by the patient. Sensorscan provide signals to a suitable controller that uses a control routineto regulate the supply of electrical energy to active and indifferentelectrodes of the iontophoresis system. For example, the controller canbe configured to supply current to the electrodes until it determinesbased on the sensor signal(s) that a desired dose of the therapeuticagent has penetrated into the body portion. A controller can also usethe sensor signals to control auxiliary devices that enhance delivery ofthe therapeutic agent to the patient.

In still another aspect, acoustic energy and a topical therapeutic agentare sequentially applied to a body portion of a patient. For example, inone embodiment, acoustic energy is applied before applying thetherapeutic agent; and in another embodiment, acoustic energy is appliedafter applying the therapeutic agent. Such sequencing is thought toallow for more precise dosing of the therapeutic agent and/or improvethe conditions for accurately monitoring the amount of therapeutic agentthat is delivered. The therapeutic agent can be applied with or withoutthe aid of iontophoresis.

Other objects and features will be in part apparent and in part pointedout hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of an iontophoresis system;

FIG. 2 is a schematic diagram of the iontophoresis system mounted on abody portion of a patient;

FIG. 3 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 4 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 5 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 6 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 7 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 8 is a schematic diagram of the iontophoresis system of FIG. 7mounted on the body portion;

FIG. 9 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 10 is a schematic diagram of another embodiment of an iontophoresissystem mounted on the body portion;

FIG. 11 is a cross section of another embodiment of an iontophoresissystem illustrated schematically;

FIG. 12 is a plan view of the iontophoresis system of FIG. 11illustrated schematically;

FIG. 13 is a perspective of the iontophoresis system of FIG. 11partially wrapped around a body lumen of a patient illustratedschematically;

FIG. 14 is a schematic block diagram of another embodiment of aniontophoresis system;

FIG. 15 is a schematic block diagram of another embodiment of aniontophoresis system;

FIG. 16 is a schematic diagram of another embodiment of an iontophoresissystem;

FIG. 17 is a schematic diagram of another embodiment of an iontophoresissystem; and

FIG. 18 is a schematic elevation of an acoustic system delivering atherapeutic agent to a body portion.

Corresponding reference characters indicate corresponding partsthroughout the drawings.

DETAILED DESCRIPTION

Systems for delivering a therapeutic agent to a patient are describedherein. In general, the systems use one or both of iontophoresis andsonophoresis to administer therapeutic agents to a patient. It iscontemplated that the delivery systems described below are commonly usedin the transdermal delivery of therapeutic agents to a body portion of apatient. That is, the systems are operative to deliver a therapeuticagent from a location outside the patient's skin into the skin orthrough the skin to an internal body part (e.g., muscle, internalorgans, blood vessels, etc.). It will be understood, however, that thesesystems may also be used in invasive procedures, such as in a surgicalsetting, to cause a therapeutic agent to penetrate a location in apatient's tissue that is not accessible. As will be discussed in furtherdetail below, the various delivery systems described herein can includeuser friendly features that improve dosing certainty in iontophoresisand sonophoresis administrations of a therapeutic agent.

Referring to FIG. 1, an iontophoresis system is generally indicated at10. As will be discussed in further detail below, the iontophoresissystem 10 is suitably configured as an all-in-one and preloaded systemfor delivering a therapeutic agent to target tissue of a patient.Although the illustrated embodiment is an all-in-one and preloadediontophoresis system, it will be understood that other types oftherapeutic delivery systems can be used in other embodiments, andcertain suitable embodiments of such other systems are described infurther detail below. The iontophoresis system 10 includes a housing 12(broadly, a support) that supports system electronics 14, an activeelectrode 16, an inactive electrode 18, electrical couplers 20, 22, anda surface mount 24. A suitable housing 12 can define one or moreenclosures for receiving the various components of the iontophoresissystem 10. In one or more embodiments, the housing 12 supports a controlinput (not shown) (e.g., a switch or a button, etc.) for selectivelycontrolling one or more aspects of the electronics 14 and/or operatingthe iontophoresis system 10. In certain embodiments, the housing 12supports the components of the iontophoresis system 10 in a fullyoperational configuration, such that the system can, for example,provide transdermal delivery of one or more therapeutic agents to targettissue in a patient using only the control inputs and without assemblingthe system in any manner. In one or more embodiments, system 10 mayinclude more than one housing for one or more of the components of thesystem.

Although the illustrated housing 12 is generally rectangular in shape,housings of other shapes may also be used in various embodiments of theiontophoresis system 10. In the illustrated embodiment, the systemelectronics 14 are supported in a proximal end portion 12A of thehousing 12 and the active and inactive electrodes 16, 18 are spacedapart toward a distal end portion 12B. The electrical couplers 20, 22extend from the active and inactive electrodes 16, 18, respectively,through the distal end portion 12B of the housing 12 so that distal endsof the couplers are located outside the housing. The surface mount 24 issecured to the distal end 12B of the housing 12 for selectively mountingthe iontophoresis system 10 on a body portion B of a patient (FIG. 2)(e.g., adjacent a patient's skin). A suitable housing 12 may be aone-piece body or a multiple piece assembly. Preferably, the housing 12includes mounting structures for holding the components of theiontophoresis system 10 within and/or on the housing. A plasticinjection molding process may be used to form the housing 12 in one ormore suitable embodiments.

The electronics 14 include an electrical power supply 26 that maysuitably comprise current control circuitry. The system electronics 14can also include various other components such as one or morecontrollers, monitoring systems, communications hardware, displays, etc.In one or more embodiments, the power supply 26 is a monopolar powersupply, for example, a direct current (DC) power supply, that has apositively charged terminal and a negatively charged terminal. Either ofthe positively or the negatively charged terminals can be connected tothe active electrode 16, and the other of the terminals is connected tothe indifferent electrode 18. In use, the power supply 26 creates avoltage difference at the electrodes 16, 18 and a closed circuit whenthe electrodes are each coupled to the same electrically conductivesurface. As discussed below, the active electrode 16 typically functionsto drive the therapeutic agent into the body portion B and theindifferent electrode functions to complete the circuit. In one or moreembodiments, the power supply 26 is a disposable battery. For example,the power supply 26 can suitably be a film battery, which occupiesminimal space in the housing 12. Such a battery may enable the housing12 to have smaller exterior dimensions than other, larger batteries. Inother embodiments, the power supply can comprise a capacitor. In one ormore embodiments, the size of the power supply 26 is minimized bylimiting the capacity to that required for delivering a single dose of atherapeutic agent using iontophoresis. In other embodiments, thecapacity of the power supply 26 is limited to that required fordelivering a predetermined number of doses that corresponds with anamount of therapeutic agent that is preloaded into the iontophoresissystem 10. As discussed below, other iontophoresis systems may includereusable electronics, in which case a reusable battery and acorresponding charging circuit may be used for the power supply.

As discussed above, the active electrode 16 and the indifferentelectrode 18 are operatively connected to the electronics 14 and powersupply 26. The active electrode 16 can be an anode that is connected tothe positively charged terminal of the power supply 16 or a cathode thatis connected to the negatively charged terminal of the power supply,depending on the type of therapeutic agent that is being used. If apositively charged therapeutic agent is used, the active electrode 16 isthe anode; and if a negatively charged therapeutic agent is used, theactive electrode is the cathode. In reusable systems, the electronicscan include a switch or an automatic controller configured to selecteither the anode or the cathode to be the active electrode, depending onwhether the therapeutic agent is positively or negatively charged. Theindifferent electrode 18 has the opposite charge of the active electrode16.

Each of the electrodes 16, 18 is connected to a respective coupler 20,22 for electrically coupling the electrode with a body portion B of apatient. Although the couplers 20, 22 are shown separately from theelectrodes 26, 18 in the drawings, it will be understood that theelectrodes can be constructed to integrally include a suitable coupler.In one or more embodiments, one or both of the electrical couplers 20,22 comprise a skin contact for creating an electrical connection betweena node of a circuit and a patient's skin. Other types of electricalcontacts that electrically connect the electrodes 16, 18 with otherbodily surfaces of a patient are also contemplated. For example, in oneor more embodiments, the couplers 20, 22 are mucous membrane contactssuitable for electrical contact with a mucous membrane of a patient.Still other types of electrical contacts may also be used in otherembodiments. When the couplers 20, 22 connect the electrodes 16, 18 tothe body portion B, the power supply 26 functions as a voltage sourceand the body portion functions as a resistor in a closed circuit.

The active electrode coupler 20 includes a therapeutic agent reservoir28. The reservoir 28 contains one or more ionic therapeutic agents. Apatient or other user is not required to load the therapeutic agent intothe reservoir 28 after manufacture of the system 10 before use. Thus,the illustrated all-in-one iontophoresis system 10 is “preloaded” with atherapeutic agent. Suitably, the reservoir 28 can be configured toprevent the preloaded therapeutic agent from escaping the reservoirprior to use. For example, the illustrated iontophoresis system 10includes a cover comprising a release strip 30 (e.g., a tamper proofrelease strip 30, broadly tamper proof packaging) that covers the distalend portion 12B of the housing, including the open distal end or outletof the reservoir 28. The release strip 30 can be removed from theoutlet, but not necessarily from the device, prior to use to dispensethe therapeutic agent from the reservoir during iontophoresis.

The reservoir 28 positions the therapeutic agent between the activeelectrode 16 and body portion B in use so that the active electrode canimpart an electromotive force that drives the therapeutic agent into thebody portion B. Before use, the reservoir 28 can, suitably, position thetherapeutic agent in fluid communication with the active electrode 16 orin spaced apart relationship with the active electrode to prevent anundesired chemical reaction. During use, however, the active electrode16 should be in electrical communication with the therapeutic agent inthe reservoir 28. FIG. 3 shows another embodiment of the iontophoresissystem 10′ that includes a second release strip 32′. The release strip32′ is positioned between the active electrode 16′ and the reservoir 28′prior to use to prevent fluid communication between the active electrodeand therapeutic agent. Immediately before use, the release strip 32′ isremoved to connect the active electrode 16′ with the therapeutic agentreservoir 28′. The release strip 32′ could be used in combination with aspring or other force mechanism (not shown) that urges the electrode 16′and reservoir 28′ into fluid communication after the release strip isremoved.

Referring again to FIGS. 1 and 2, any suitable reservoir may be used tocontain the therapeutic agent. For example, in one embodiment thereservoir 28 includes an open cell foam or an absorbent fabric (e.g.,gauze) that is impregnated with the therapeutic agent. Suitably, theabsorbent structure defines one or more flow passages that promotedistal capillary flow of the therapeutic agent toward the body portion Bin use. In other embodiments, the reservoir 28 defines an otherwiseempty chamber that is at least partially filled with the therapeuticagent.

Suitably, the reservoir 28 can be configured to ensure localadministration of the therapeutic agent. For example, the reservoir 28can include a sealing structure (not shown) that extendscircumferentially around an outlet opening. The sealing structure can bearranged so that the therapeutic agent passes through the sealingstructure before being delivered to the body portion B. The sealingstructure is configured to form a substantially liquid and/or fluidtight seal with the outer surface of the body portion B (e.g., the skin,a mucous membrane, etc.). The interior of the circumferential sealingstructure thereby defines a local administration area. In use thetherapeutic agent is driven into the body portion B at the localadministration area and the circumferential seal prevents thetherapeutic agent from flowing through the seal into contact withanother area of the outer surface of the body portion. In one or moreembodiments, the size of the local administration area can be adjustedto correspond with a particular treatment region. For example, the localadministration could be sized to substantially correspond with a desiredbody part such as a biological lumen or organ (e.g., a vein, an artery,a specified muscle group, etc.). In use, the housing 12 is placed on thebody portion B so that the local administration area substantiallyaligns with the desired body part and iontophoresis directs thetherapeutic agent to the desired body part in a targeted manner.

Various therapeutic agents may be preloaded into the fluid reservoir 28.Suitably, a therapeutic agent may be a water soluble, ionic substance inan aqueous solution. Another therapeutic agent that is particularlywell-suited to hyperhidrosis treatment is plain tap water. Therapeuticagents that are soluble in solvents other than water may also be used inother embodiments. For example, in one or more embodiments, thetherapeutic agent is a dissolved component of a dimethyl sulfoxide(DMSO) solution. In some embodiments, the therapeutic agent, itself, maynot be an ionic substance (e.g., a therapeutic agent comprising alipid), but the solvent that carries that therapeutic agent is an ionicsubstance. It is believed that, as the electrical field generated by theiontophoresis system 10 drives the ionic solvent into the body portionB, the solvent can carry certain non-ionic therapeutic agents with it toadminister the therapeutic agent to the patient. In still otherembodiments, the therapeutic agent may be carried by a gel or paste. Insuitable embodiments, the therapeutic agent is an active compound with atherapeutic effect (e.g., anesthetic, relaxant, anti-inflammatory,analgesia, blood flow stimulant, antiseptic, sweat suppressant,antibiotic, cosmetic, tissue reconstruction, antipuritic, etc.).Exemplary therapeutic agents include Acetic Acid, Calcium Chloride,Dexamethasone, Hydrocortisone, Hydrocortisone Prednisone, Iodine,Lidocaine, Magnesium Sulfate, Hyaluronidase, Salicylates, TolazolineHydrochloride, Zinc Oxide, chemotherapeutic agents, tap water, menthol,Diclofenac, etc.

In the illustrated embodiment, the mount 24 includes a temporaryadhesive at the distal end portion 12B of the housing 12. The releasestrip 30 temporarily covers the adhesive 24 prior to use and can beremoved to expose the adhesive. It will be understood that other mountsfor mounting the iontophoresis system in operative engagement with abody portion B may also be used in other embodiments. For example, thehousing 12 could be constructed so that, when the housing is pressedagainst a surface of a body portion B, the housing passively creates avacuum in an interior chamber (e.g., like a suction cup) that holds theiontophoresis system 10 in operative connection with the body portion ofthe patient. The adhesive 24 is configured to secure the housing 12 tothe body portion B so that the couplers 20, 22 are operatively connectedto the outer surface of the body portion. For example, when the adhesive24 properly secures the housing 12 to the body portion B, the couplers20, 22 contact the body portion and the reservoir 28 is positioned influid communication with the body portion.

To use the iontophoresis system 10, a user removes the release strip 30and secures the housing 12 to the body portion B of the patient usingthe mount 24. The user does not load the therapeutic agent into theiontophoresis system 10 prior to use, as the system is preloaded atmanufacture. The mount 24 holds the iontophoresis system 10 so that thecouplers 20, 22 electrically couple the active electrode 16 and theindifferent electrode 18 to the body portion B to create a closedcircuit. The user can then operate the control input (not shown) on thehousing 12 to activate the electronics 14. For example, by activatingthe iontophoresis system 10, the user can cause the power supply 26 todraw a current through the closed circuit. The power supply 26 willpositively charge the active electrode 16 if the therapeutic agent is apositively charged ion or negatively charge the active electrode if thetherapeutic agent is a negatively charged ion, thus repelling thetherapeutic agent distally toward and into the body portion B. As shownin FIG. 2, the electrical repulsion causes the therapeutic agent topenetrate deeply into the tissue. The active electrode 16 may continueto repel the similarly charged ions of the therapeutic agent into thebody portion B until a dose of the therapeutic agent has been delivered.If the iontophoresis system 10 is a single dose system, it can beremoved and disposed of after the dose has been delivered. If theiontophoresis system 10 is a multi-dose system, it can optionally remainmounted on the patient or removed between administrations of doses.

In one or more embodiments, the electronics 14 include a controller thatautomatically controls the administration of the therapeutic agent toensure the delivery of one or more complete doses. For example, thecontroller can automatically shut off the power supply 26 after apredetermined amount of time that is known to empirically correspondwith a complete delivery of a dose of the therapeutic agent. In certainembodiments, this time period can be specifically configured for thesubject/treatment, based on characteristics of the subject includingskin type, treatment location, age, and/or therapeutic agent, etc. Insome embodiments, the controller can be further configured toautomatically administer multiple doses of the therapeutic agent byswitching the power supply on after a predetermined time period afterthe administration of the first dose. The iontophoresis system 10 mayinclude configuration inputs that allow the user to set the length ofthe predetermined time period between doses. In addition to usingpredetermined time periods to automatically control the dosing oftherapeutic agents, other control variables may also be used asdiscussed in further detail below.

Thus, it can be seen that the all-in-one and preloaded iontophoresissystem 10 is a user-friendly device. The iontophoresis system 10 may beparticularly well-suited for self-administration of a therapeutic agent.Because the system 10 is preloaded with the desired dose of thetherapeutic agent and the electronics 14 can be configured toautomatically control delivery of a complete dose, the system minimizesthe likelihood of user error.

Referring to FIG. 4, another embodiment of a preloaded iontophoresissystem is generally indicated at 110. Like the iontophoresis system 10,the iontophoresis system 110 includes electronics 114 comprising a powersupply 126, an active electrode 116, an indifferent electrode 118,couplers 120, 122, a preloaded therapeutic agent reservoir 128, and asurface mount 124. Unlike the iontophoresis system 10, the iontophoresissystem 110 includes first and second selectively separable modules 112,113 that separately support certain components. The first module 112 isthe electronics module that supports the system electronics 114, and thesecond module 113 is the administration module that supports theelectrodes 116, 118, couplers 120, 122, reservoir 128, and surface mount124. In the illustrated embodiment, the electronics module 112 isconfigured to be mounted on the administration module 113. Although FIG.4 schematically illustrates a bayonet connection, any suitable mountingstructure can be used to mount the electronics module 112 onto theadministration module 113 (e.g., threaded connectors, mechanicallyinterlocking structures, etc.). In addition, each of the modules 112,113 includes respective electrical connectors 132, 134 for connectingthe active electrode 116 and the indifferent electrode 118 to theterminals of the power supply 116. In certain embodiments theelectronics module 112 is electrically connectable to the administrationmodule 113 but is not structurally mountable thereupon. For example,lead wires can connect the electronics module 112 to the administrationmodule 114 in certain embodiments. In one such embodiment, theadministration module 113 is a bandage-type patch.

The electronics module 112 may be configured for reuse while theadministration module 113 may be disposable and/or one-time use. Forexample, each administration module 113 may be preloaded with a singledose of therapeutic agent or another number of doses. The electronicsmodule 112 can be connected to the administration module 113 and used toadminister the therapeutic agent that is preloaded in the reservoir 128as described above. Then, once the reservoir 128 is depleted, the usercan remove the electronics module 112 from the administration module 113and dispose of the administration module. When additional therapeuticagent is needed, the user can mount the electronics module 112 on a newadministration module 113. Like the iontophoresis system 10, theiontophoresis system 110 uses features such as a preloaded reservoir 128and system electronics 114 that provide dosing control in auser-friendly device for administering specified doses of therapeuticagent. But in addition, the iontophoresis system 110 is thought to belower cost than the iontophoresis system 10 because the components ofthe electronics module 112 can be reused and only the administrationmodule 113 needs to be replaced after each use. Moreover, theelectronics module 112 can be constructed with more robust componentsthat may have a higher cost because the module is configured for reuse.

Referring to FIG. 5, another embodiment of a preloaded iontophoresissystem is generally indicated at 210. Like the iontophoresis system 110,the iontophoresis system 210 includes an electronics module 212 and aselectively separable administration module 213. But unlike theiontophoresis system 110, the electronics module 212 of theiontophoresis system 210 includes the indifferent electrode 218 and thecoupler 222, as well as the system electronics 214 and included powersupply 226. Thus, the administration module 213 includes the activeelectrode 216, the coupler 220, and the preloaded therapeutic agentreservoir 228. An electrical connector 232 is configured to connect theactive electrode 216 to the system electronics 214. The electronicsmodule 212 can optionally be configured to be mounted on theadministration module 213 or merely electrically connected through awired connection. In a suitable embodiment, the electronics module 212can be mounted on the administration module 213 so that the indifferentelectrode coupler 222 aligns with the active electrode coupler 220 suchthat each of the couplers is operatively connected to the body portion Bwhen the surface mount 224 mounts the iontophoresis system 210 on thebody portion. In one or more embodiments, the administration module 213is disposable and the electronics module 212 is reusable. As comparedwith the iontophoresis system 110, the iontophoresis system 210 may havean even lower cost because more of the components are reusable.

Referring to FIG. 6, in another embodiment, an iontophoresis system 310maximizes the number of reusable components. The iontophoresis system310 includes a housing 312 that supports system electronics 314, a powersupply 326, an active electrode 316, an indifferent electrode 318, anindifferent electrode coupler 322, and a surface mount 324. The housing312 defines a cavity 334 for receiving and operatively positioning adisposable, preloaded therapeutic agent cartridge 328. The therapeuticagent cartridge 328 is preloaded with one or more doses of therapeuticagent. The cartridge 334 can include one or more removable structures(e.g., lids, release strips, wrappers, etc.) that contain thetherapeutic agent in the cartridge 334 prior to use. Before thecartridge 328 is loaded into the cavity 334, these removable structuresare removed so that the therapeutic agent can be delivered from thecartridge to the body portion B using iontophoresis. In one or moreembodiments, the replaceable cartridge 328 functions as a coupler forelectrically coupling the active electrode 316 with the body portion Bof the patient. After the therapeutic agent in one cartridge 328 hasbeen delivered, a user can dispose of the spent cartridge and refill thecavity 334 with a new cartridge. Although the illustrated embodiment,shows the replaceable cartridge 328 being usable with an all-in-oneiontophoresis system it will be understood that the replaceablecartridge could be used with a modular iontophoresis system withseparate reusable electronics and administration modules. In one or moresuitable embodiments the surface mount 324 is reusable and/orreplaceable after each use. For example, replaceable adhesive strips canbe applied to the distal end of the housing 312 each time it is mountedon the body portion B. An exemplary reusable surface mount is alsodiscussed in further detail below.

Referring to FIGS. 7 and 8, another embodiment of an iontophoresissystem is generally indicated at 410. Like the iontophoresis system 10,the iontophoresis system 410 includes a housing 412 that supports anactive electrode 416, an indifferent electrode 418, electrode couplers420, 422, and a fluid reservoir 428, which may be preloaded or fillable.Unlike the housing 12, the housing 412 is generally dome-shaped, but thehousing could have other shapes without departing from the scope of theinvention. For example, rather than a rigid housing 412, the activeelectrode 416, indifferent electrode 418, couplers 420, 422, and fluidreservoir 428 could be supported by one or more flexible patchescomprising fluid impermeable backing(s) configured for engaging the bodyportion B and forming a fluid-tight seal therewith. An air fitting 440and electronics connector 442 extend through a proximal wall of thehousing 412 (or fluid impermeable backing). A distal end portion of thehousing 412 defines a circumferential rim 444 that is configured forcontinuous circumferential engagement with the body portion B in use.Where a flexible patch or patches are used in lieu of the housing 412,the patches can comprise an adhesive or other sealing structure thatextends circumferentially around one or more of the components of theiontophoresis system 410 that are configured for operative engagementwith the body portion B. In addition, the adhesives could be positionedon a semipermeable membrane extending over the reservoir 428. It isunderstood that a semipermeable membrane supporting an adhesive could beused with any of the iontophoresis systems discussed herein.

In the illustrated embodiment, the system electronics 414 are locatedremote from the housing 412 in a separate module. However, all or someof the system electronics could be supported by the housing 412 in otherembodiments. As above, the system electronics include a power supply426. The opposite terminals of the power supply 426 are connected to theconnector 442 in the proximal wall of the housing 412, and internalwires carry the current from the connector to the active electrode 416and the indifferent electrode 418, respectively. In addition to thepower supply 426, the system electronics 414 includes a vacuum 446 thatis operatively connected to the air fitting 440 to apply negativepressure to the interior of the housing 412. Although the vacuum 446 islocated remote from the housing 412 in the illustrated embodiment, itcan also be mounted on or within the housing in other embodiments. Whena fluid impermeable patch or patches are used in lieu of the housing412, the air fitting 440 can operatively connect the vacuum 446 to adistal side of the fluid impermeable backing to apply negative pressureto a space between the backing and the body portion of the patient.

In use, the external system electronics 414 and vacuum 446 are connectedto the electrical connector 442 and air fitting 440, respectively. Theuser also places the housing 412 on the body portion B so that the rim444 contacts the body portion around its entire circumference to form anairtight seal. If a patch were used instead, the user would place thepatch so that a circumferential sealing structure (e.g., an adhesiveseal) forms an airtight seal around the space between the body portion Band fluid impermeable backing. Preferably, the couplers 420, 422 arepositioned within the housing 412 or on the fluid impermeable backing sothat, when the housing or patch is properly placed on the body portionB, the couplers contact the body portion to electrically couple theelectrodes 416, 418 and the body portion. Moreover, proper position ofthe housing 412 or fluid impermeable backing likewise positions thefluid reservoir 428 in fluid communication with the body portion B. Withthe housing 412 or patch(es) in the proper position, the user activatesthe system electronics 414. In a suitable embodiment, the systemelectronics 414 automatically causes the vacuum 446 to draw air throughthe air fitting 440 before activating the power supply 426 to beginiontophoresis. As shown in FIG. 8, as the vacuum 446 draws in air andnegative pressure in the interior of the housing 412 increases, thehousing is pulled tighter against the body portion B. When using thehousing 412, the negative pressure in the interior eventually reaches alevel that secures the housing to the body portion B without anyadditional holding force. In one embodiment, the system electronics 141determine when sufficient vacuum pressure is established by monitoringan impedance of the body portion B. This can also be true when using theflexible patch(es), or the flexible patch(es) can be held against thebody portion B using a mounting structure such as an adhesive. At thispoint the system electronics (either automatically or at the directionof the user) turns on the power supply 426 to begin iontophoresis.Suitably, the electronics 414 can include a controller that isconfigured to determine when the negative pressure in the housinginterior is sufficient to mount the iontophoresis system 410 on the bodyportion (e.g., using a sensor) and to prevent the power supply fromsupplying current to the electrodes 416, 418 until that time. Thereservoir 420 can include a sealing structure at the distal end forforming a sealed interface with the subject. The sealing structure canextend along the rim of the reservoir 420 around an opening or permeablemembrane through which the therapeutic agent is discharged from thereservoir in use. The sealing structure inhibits therapeutic agent fromflowing along the surface of the body portion of the subject withoutpenetrating into the tissue to prevent the therapeutic agent fromshort-circuiting the current flow by forming a direct electrical pathwayalong the surface of the body portion between the active and indifferentelectrodes 416, 418.

The iontophoresis system 410 using the housing 412 is particularly wellsuited to administering the therapeutic agent to a body portion B thathas a mucous membrane. It is difficult to secure an administrationmodule of an iontophoresis system to a mucous membrane using an adhesivemount. However, the above-described negative pressure mount is notaffected by the moisture of the mucous membrane. Moreover, the use ofnegative pressure draws the body portion proximally into the interior ofthe housing 412 to create closer and more secure contact with thecouplers 420, 422.

The iontophoresis system 410 may also be used in a wound treatmenttherapy, such as a therapy for the treatment of diabetic ulcers or otherchronic wounds. In these embodiments, the housing or patch is placedover a wound (e.g., ulcer) so that the fluid reservoir is fluidlycoupled with the wound and the housing or patch seals against the bodyportion B to define a sealed space between the housing or patch and thebody portion B. The vacuum 446 draws a negative pressure in the space,which applies negative pressure therapy to the wound. Then, while thewound is being treated with negative pressure therapy, a suitabletherapeutic agent is delivered to the wound using iontophoresis. Certaintherapeutic agents that are thought to be suitable for wound treatmentinclude saline, antibiotics, antimicrobials, retapamulin, hydrogels,hydrocolloids, alginates, collagenase, etc. Thus, using theiontophoresis system 410, iontophoresis may be combined with negativepressure wound treatment to enhance treatment of the wound.

As shown in FIG. 9, in certain embodiments, the iontophoresis system 410can be configured so that the reservoir 428 is a disposable cartridgecontaining the therapeutic agent, and the housing 412 is configured tooperatively mount the disposable cartridge for dispensing thetherapeutic agent using iontophoresis. In addition, the iontophoresissystem 410 can likewise be configured as an all-in-one preloadediontophoresis system or preloaded administration module of aniontophoresis system in other embodiments. For example, the flexiblepatches discussed above may be disposable administration modules thatare preloaded with one or more doses of a therapeutic agent.

Referring to FIG. 10, another embodiment of an iontophoresis system isgenerally indicated at 510. The iontophoresis system 510 includes anactive electrode 516, an indifferent electrode 518, and respectivecouplers 520, 522. External system electronics 514 include a powersupply 526 and wires that connect the power supply to the electrodes516, 518. Each of the electrodes 516 and 518 and its respective coupler520, 522 is mounted on a separate patch 512, 513. The patches 512, 513each include an adhesive strip 524 for operatively mounting the patcheson a body portion B of the patient. In the illustrated embodiment, thepatches 512, 514 are separable to allow each of the electrodes 516, 518to be operatively connected to an opposing surface of the body portionB. In one or more embodiments, the patch 512 includes a reservoir 528that is preloaded with one or more doses of a therapeutic agent.

In certain methods of using the iontophoresis system 510, the patches512, 513 are operatively mounted on the body portion B so that theindifferent electrode 518 opposes the active electrode 516. For example,in one or more embodiments, the patches 512, 513 are mounted atdiametrically opposed positions on the body portion B. The opposingrelationship is thought to improve penetration of the therapeutic agentinto the body portion B by utilizing the attractive forces of thecharged indifferent electrode 518, as well as the repulsive forces ofthe oppositely charged active electrode 516. For example, as shown inFIG. 10, the active electrode 516 imparts a repulsive electromotiveforce F1 upon the therapeutic agent, which has the same charge as theactive electrode. In addition, the indifferent electrode 518, which hasan opposite charge, imparts an electromotive force F2 upon thetherapeutic agent that tends to draw the therapeutic agent toward theindifferent electrode. The electromotive forces F1 and F2 are thought toact in combination upon the ionic therapeutic agent to drive thetherapeutic agent further into the body portion B than the activeelectrode 514 acting alone, thus providing more confidence in completedosing.

Referring to FIGS. 11 and 12, an iontophoresis patch is generallyindicated at 612. The iontophoresis patch 612 is suitably configured tobe connected to an external power supply (not shown). The iontophoresispatch 612 includes a one-piece base 613 that has a first end portionthat supports an active electrode 616 and a coupler 620 and a second endportion that supports an indifferent electrode 618 and a coupler 522.Adhesive mounts 624 extend around each of the couplers 620, 266 forsecuring respective end portions of the patch 612 to a body portion B.The iontophoresis patch 612 further includes a reservoir 628 that can bepre-loaded with a therapeutic agent or filled with a therapeutic agentby a user.

The base 613 of the patch 612 includes an elongate central portion thatextends between the first and second end portions. As a result, theactive and indifferent electrodes 614, 616 are spaced apart by adistance D. In one or more embodiments, the distance D is between about40% and about 60% (e.g., about 50%) of a circumference of a body portionB. Thus, when the patch 612 is wrapped circumferentially around the bodyportion B and mounted thereupon, the active and indifferent electrodes616, 618 generally oppose one another to enhance penetration of thetherapeutic agent into the body portion.

Referring to FIG. 13, in one or more embodiments, the body portion B isa body lumen such as a vein or an artery. The patch 612 is, therefore,sized and arranged for mounting active and indifferent electrodes 614,616 in opposing relationship with respect to the body lumen. It will beunderstood that the patch 612 can be sized and arranged for use withother types of body portions (e.g., legs, arms, hands, fingers, toes,feet, etc.) in other embodiments. Moreover, it will be understood thatother types of iontophoresis patches can be mounted on a body lumen(e.g., those configured to mount the active and indifferent electrodesin spaced apart relationship along the axis of the lumen) in otherembodiments.

Referring to FIG. 14, another embodiment of an iontophoresis system isgenerally indicated at 710. The iontophoresis system 710 includes apatch 712 that supports an active electrode 716 and an indifferentelectrode 718. The patch 712 also supports an active electrode coupler720 and an indifferent electrode coupler 722 configured to electricallycouple the active electrode 716 and the indifferent electrode 718 to abody portion B when the patch is mounted on the body portion. The patch712 further includes adhesive mounts 724 configured to mount the patch712 on the body portion B so that each of the couplers 720, 722 areoperatively connected to the body portion. The patch 712 supports atherapeutic agent reservoir 728 that can be preloaded with a therapeuticagent or filled with a therapeutic agent by a user. As discussed infurther detail below, the patch 712 also supports one or more auxiliarydevices 750 that are configured to be operatively connected to the bodyportion B of the patient and/or the reservoir 728 to enhance delivery ofthe therapeutic agent to the patient.

The illustrated iontophoresis system 710 includes an externalelectronics module 714, but the electronics module and other componentsof the system could be supported together by a single structure (e.g., apatch, a housing, etc.) in other embodiments. The electronics module 714includes a power supply 726 and a controller 748. The controller 748 isconfigured to control the power supply 726 to selectively deliver powerfrom the power supply to the electrodes 716, 718 to use theiontophoresis to deliver one or more doses of the therapeutic agent tothe body portion B. In addition, the controller 748 is configured to beoperatively connected to the auxiliary device 750 to control theoperation of the auxiliary device. The power supply 726 is alsooperatively connected to the auxiliary device 750 to supply power to theauxiliary device in suitable embodiments.

In one exemplary embodiment, the auxiliary device 750 is a heater. Forexample, the auxiliary device 750 could be a resistive heater, anultrasound generator, or any other suitable kind of heater. In oneapplication, the heater can be operatively connected to the reservoir728 to heat the therapeutic agent to a desired temperature. For example,the controller can be configured to operate the heater 750 to maintainthe temperature of the therapeutic agent at the desired temperature. Inaddition, the controller 748 could be configured to prevent the system710 from delivering electrical energy from the power supply 726 to theelectrodes 716, 718 until after the therapeutic agent is heated to adesired temperature. In another embodiment, the heater 750 can beconfigured for operative connection with the body portion B of thepatient when the patch 712 is mounted on the patient. The controller 748can, for example, operate the heater 750 to increase the temperature ofthe body portion B above normal levels prior to and/or duringiontophoresis. It is believed that increasing the temperature of thebody portion B can widen pores or produce cavitation in the body portionand thereby increase the size and number of the pathways through whichthe therapeutic agent travels during use. Although the illustratedembodiment uses a controller 748 in a remote electronics module 714 tooperate the heater 750 it will be understood that the heater could besubject to local control (e.g., using a local thermostat) withoutdeparting from the scope of the invention.

In another embodiment, the auxiliary device 750 includes a chiller. Thechiller 750 can be operatively connected to one or both of the fluidreservoir 728 and the body portion B to decrease temperature. Suitably,the controller 748 can be operatively connected to the chiller 750 tooperate the chiller to enhance delivery of the therapeutic agent to thebody portion B or enhance the therapeutic effect of the agent in anotherway (e.g., by chilling the therapeutic agent to an active temperature).In one embodiment, the patch 712 supports both a heater and a chiller(e.g., a Peltier pump) that are operatively connected to the bodyportion B. In use, the controller 748 is suitably configured to cyclebetween heating the body portion B and cooling the body portion to openand close the pores in alternating fashion. It is thought that openingand closing pores may enhance a capillary action by which thetherapeutic agent can be absorbed into the body portion B.

In still another embodiment, the auxiliary device 750 includes avibrator. The vibrator can be operatively connected to the body portionB to vibrate the tissue. Suitably the controller 748 can be operativelyconnected to the vibrator 750 to operate the vibrator to enhancedelivery of the therapeutic agent to the body portion B or enhance thetherapeutic effect of the agent in another way (e.g., by agitating thetherapeutic agent prior to use). For example, in one or moreembodiments, the controller 748 is configured to selectively operate thevibrator 750 to vibrate the body portion B in order to work thetherapeutic tissue deeper into the pores and/or shake loose matter thatis obstructing the pores.

In yet another embodiment, the auxiliary device 750 is a magnetic fieldgenerator. The magnetic field generator 750 can be operatively connectedto the body portion B to create a magnetic field in the tissue. Themagnetic field generator 750 may be used with a magnetically chargedtherapeutic agent in a similar way to an iontophoresis system to drivethe therapeutic agent into the body portion B. In suitable embodiments,the fluid reservoir 728 is filled with a therapeutic agent that has bothan electrical charge and a magnetic charge so that the magnetic fieldgenerator 750 works in combination with the iontophoresis system 710 todrive the therapeutic agent into the body portion. In other embodiments,the fluid reservoir 728 contains at least a first therapeutic agent thathas an electrical charge and a second therapeutic agent that has amagnetic charge. The iontophoresis system 710 drives the electricallycharged therapeutic agent into the body portion B and the magneticgenerator 750 drives the magnetically charged therapeutic agent into thebody portion. In yet another embodiment, the therapeutic agent has onlya magnetic charge. A magnetic generator can be used withoutiontophoresis to drive the therapeutic agent into the body portion.Suitably, the magnetic generator can be attached to a surface mountconfigured for mounting the generator on the body portion andoperatively connected to a power supply that provides power. Inaddition, the magnetic generator is positioned relative a therapeuticagent reservoir to generate a magnetic field that passes through thereservoir and into the body portion. The reservoir can be preloaded orfilled by a user with the magnetically charged therapeutic agent.

With continued reference to FIG. 14, in another embodiment, theauxiliary device is an acoustic energy generator. The acoustic energygenerator can be an ultrasound generator or another acoustic energygenerator configured to generate acoustic energy with a frequency of,for example, at least about 15 kHz. In a suitable embodiment, theultrasound generator 750 is operatively connected to the body portion Bto apply an ultrasound to the body portion. For example, an ultrasoundgel may couple the acoustic energy generator 750 to the body portion B.In general, acoustic energy (e.g., focused ultrasound) can increasecavitation in tissue, and thus improve permeability for drug delivery.Acoustic energy can also aid in driving a therapeutic agent into tissue.For example, low intensity collimated beam ultrasound can increase bloodflow to a treatment site and/or open pores of the subject. Moreover,focused ultrasound energy can be used to specifically target definedlocations within the tissue in which to cause cavitation. By using theacoustic energy generator 750 to apply acoustic energy before, during,and/or after iontophoresis, delivery of the therapeutic agent is thoughtto be enhanced. In one aspect, the combination of acoustic energy fromthe auxiliary device 750 and iontophoresis from the system 710 isthought to enhance delivery by causing the drug to penetrate deeper intothe tissue of the body portion B. In another aspect, the combination ofacoustic energy from the auxiliary device 750 and iontophoresis from thesystem 710 is thought to enhance delivery by ensuring a largerpercentage of the total applied therapeutic agent is delivered into thetissue of the body portion B.

The controller 748 can be configured to automatically sequence theoperation of the acoustic energy generator 750 with the applicationiontophoresis to optimize delivery of the therapeutic agent. Forexample, in certain embodiments, the controller 748 is configured tocause the acoustic energy generator 750 to apply acoustic energy to thetissue of the body portion B before applying iontophoresis. In this way,the tissue is sonicated before the therapeutic agent is applied. Inanother embodiment, the controller 748 is configured to cause theacoustic energy generator 750 to apply acoustic energy to the tissue ofthe body portion B simultaneously with iontophoresis. In still anotherembodiment, the controller 748 is configured to cause the acousticenergy generator 750 to apply acoustic energy to the tissue of the bodyportion B after iontophoresis. This sequence may allow drug flow throughthe tissue to continue even after iontophoresis is complete. Asdiscussed in further detail below, acoustic energy and iontophoresis maybe sequenced so that the therapeutic agent need not be administered inan acoustic coupling gel, as with conventional sonophoresis techniques.

Although the auxiliary devices 750 discussed above were described in thecontext of an iontophoresis patch 710, it will be understood that theycould be used alone or in combination in any of the iontophoresissystems 10, 110, 210, 310, 410, 510, 610 discussed above or additionalsystems discussed below.

Referring to FIG. 15, another iontophoresis system is generallyindicated at 710′. The features of the iontophoresis system 712 givenreference numbers above are given the same reference number in FIG. 15,followed by a prime symbol. The iontophoresis system 710′ issubstantially similar to the iontophoresis system 710, except for thedifferences noted hereinafter. Specifically, whereas the system 710includes an auxiliary device 750 that is supported by the patch 712, anauxiliary device 750′ of the system 710′ is included in the externalelectronics module 714′. The system 710′ includes an auxiliary inputtransmission line 751′ that is configured to transmit the auxiliaryinput to an auxiliary input coupler 752′ supported by the patch 712′.Thus, the auxiliary device 750′ generates the auxiliary input andtransmits the auxiliary input over the transmission line 751′ to thecoupler 752′, which operatively couples the auxiliary input to thereservoir 728′ and/or body portion B. Any suitable auxiliary device,such as the auxiliary devices 750 described above, may be used for theauxiliary device 750′ in combination with a suitable coupler 752′.

Referring to FIG. 16, another embodiment of an iontophoresis system isgenerally indicated at 810. The iontophoresis system 810 includes apatch 812 that supports an active electrode 816 and an indifferentelectrode 818. The patch 812 also supports an active electrode coupler820 and an indifferent electrode coupler 822. The patch 812 furtherincludes adhesive mounts 824 configured to mount the patch 812 on thebody portion B so that each of the couplers 820, 822 are operativelyconnected to the body portion. The patch 812 also supports a therapeuticagent reservoir 828 that can be preloaded with a therapeutic agent orfilled with a therapeutic agent by a user. Like iontophoresis systemsdiscussed above, the system 810 includes electronics 814, which can bemounted on the patch 812 or housed remotely, that include a power supply826 for creating an electric field that drives iontophoresis.

The iontophoresis system 810 differs from the iontophoresis systemsdiscussed above in that it includes a tissue-working structure 850 atthe active electrode coupler 820. In general, a suitable tissue-workingstructure is configured to work the tissue of the body portion B (e.g.,by abrading, puncturing, cutting, exfoliating, etc.) when the patch 812is mounted on the body portion B to promote penetration of thetherapeutic agent. In one or more suitable embodiments, thetissue-working structure includes an abrader, puncture member, cutter,and/or exfoliator, etc. The tissue-working structure 850 can beconfigured to work the tissue in the desired fashion by simply pressingthe patch 812 onto the body portion B or by moving (e.g., rubbing) thepatch across the body portion while the tissue-working structurecontacts the target tissue. Although the tissue working structure 850 isdescribed in the context of an iontophoresis patch 810, it will beunderstood that it could be used or alone or in combination in any ofthe iontophoresis systems 10, 110, 210, 310, 410, 510, 610, 710discussed above or additional systems discussed below.

In one or more embodiments, a method of using an iontophoresis systemcomprises preparing target tissue of a body portion B before usingiontophoresis to deliver a therapeutic agent to the target tissue. Forexample, any one or more of the following preparation techniques can beused alone or in combination: abrading, puncturing, cutting,exfoliating, removing hair, etc. The preparation technique(s) can beperformed by a tissue-working structure 850 that is mounted on theiontophoresis system 810 or by another, separate device.

Referring to FIG. 17, another embodiment of an iontophoresis system isgenerally indicated at 910. The iontophoresis system 910 includes apatch 912 that supports an active electrode 916 and an indifferentelectrode 918. The patch 912 also supports an active electrode coupler920 and an indifferent electrode coupler 922. The patch 912 furtherincludes adhesive mounts 924 configured to mount the patch 912 on thebody portion B so that each of the couplers 920, 922 are operativelyconnected to the body portion. The patch 912 also supports a therapeuticagent reservoir 928 that can be preloaded with a therapeutic agent orfilled with a therapeutic agent by a user. Like iontophoresis systemsdiscussed above, the system 910 includes electronics 914 (which can bemounted on the patch 912 or housed remotely) that include a power supply926 for creating an electric field that drives iontophoresis and acontroller 948 for controlling the iontophoresis process. Theelectronics 914 further include a display 960 and a communicationsinterface 962. The display 960 is configured to locally displayinformation about the administration of the therapeutic agent to theuser. The communications interface 962 operatively connects theelectronics 914 to an external database 964 to provide data from theiontophoresis system 910 to the external database. In the illustratedembodiment, the communications interface 962 is a wireless interface,but hardwired interfaces may also be used in other embodiments. Althoughan external database 964 is shown, it will be understood that a databasestored on a local memory of the electronics 914 may also be used.

The iontophoresis system 910 further includes at least one sensor 970.As discussed in further detail below, the sensor 970 can be operativelyconnected to one of the fluid reservoir 928 and body portion B to senseone or more parameters of the therapeutic agent, body portion, and/oriontophoresis process. Various types of sensors 970 can be useddepending on the parameter to be sensed. Suitable parameters may, forexample, include therapeutic agent temperature, body portiontemperature, electrical field, magnetic field, radiation, therapeuticagent flow, etc.

In one or more embodiments, the sensor 970 is operatively connected tothe controller 948 to provide a sensor signal representative of thesensed parameter to the controller. The controller 948 uses the sensorsignal to control one or more aspects of the iontophoresis process. Forexample, in certain embodiments, the iontophoresis system 910 includesan auxiliary device (not shown). The controller 948 may be configured toreceive the sensor signal from the sensor 970 and use it to control theoperation of the auxiliary device. Likewise, the controller 948 may beconfigured to receive the sensor signal and use it to control theoperation of the power supply 926.

In addition to the controller 948, the sensor 970 can also beoperatively connected to one or both of the display 960 and thecommunications interface 962. The sensor 970 can suitably be operativelyconnected to the display 960 to render information about the sensorsignal on the display. For example, if the sensor 970 is a temperaturesensor, the display 960 may provide a real time display of the sensedtemperature. If, as discussed in further detail below, the sensor 970 isconfigured to detect a parameter related to an amount of therapeuticagent that is successfully delivered, the display may provide a realtime display of the amount of therapeutic agent delivered (e.g., as apercentage of a dose). The display 960 can also provide a visualindication when a complete dose has been delivered and the system 910has been turned off. Audible indications may also be used in addition oras an alternative to visual indications. The sensor can, likewise, beoperatively connected to the communications interface 962 to store thedata from the sensor signal in the database 964. In one or moreembodiments, the database 964 is a central database that is accessibleby the patient's medical provider. The communications interface 962 cansend data from the sensor 970 to the database 964 that relates to thepatient's treatment using the iontophoresis system. This allows themedical provider to monitor a patient's progress in therapy. In certainembodiments, the medical provider can remotely alter a treatmentprotocol executed on the controller 948 based on the data theiontophoresis system 10 stores in the database. For example, if apatient is abusing the therapy, the medical provider could remotelyadjust the treatment protocol to limit the amount of therapeutic agentthat the system 910 delivers to the patient. The data may pass directlyto the external database 964 using, for example, an internet connection,or the data may be first stored on a local memory and then uploaded tothe database at a later time (e.g., when the patient returns to amedical office, etc.).

In one embodiment, the sensor 970 is configured to sense a parameterrelated to an amount of therapeutic agent delivered to the patient. Thecontroller 948 receives the sensor signal and uses it to operate thepower supply 926. For example, the controller 948 can automaticallyswitch off the power supply 926 after it determines that an entire doseof the therapeutic agent has been delivered using the sensor signal. Inone or more embodiments, the controller 948 instructs the communicationsinterface 962 to store on the database 964 an indication of an amount oftherapeutic agent delivered after each round of iontophoresis iscomplete. In certain embodiments, the controller 948 is in operativecommunication with the display 960 to provide information about anamount of therapeutic agent that has been delivered to the patient. Thedisplay 960 uses this information to, for example, generate a graphicindication representative of the progress in delivering a complete dose.In some embodiments, the controller 948 is operatively connected to anauxiliary device that is connected to the body portion B of the patientto affect the body portion in a way that enhances delivery of thetherapeutic agent. The controller 948 uses the signal from the sensor970 to selectively actuate the auxiliary device at times when the rateof delivery slows or stalls.

A suitable sensor 970 for sensing an amount of therapeutic agentdelivered to a patient may include a Geiger counter. When thetherapeutic agent is a radioactive substance such as certainchemotherapy drugs, a Geiger counter 970 may be used to measureradiation at the body portion B. The amount of detected radiation isthought to relate to the amount of radioactive drug delivered. Thus, thesignal from the Geiger counter can be used to determine an amount ofradioactive therapeutic agent that has been delivered.

Another suitable sensor 970 for sensing an amount of therapeutic agentdelivered to a patient may include an optical sensor, such as a cameraor scanner. In certain embodiments, a therapeutic agent can be opticallylabeled so that it is detectable using an optical sensor. The opticalsensor provides a signal that includes an indication of a detectedconcentration of the optical label associated with the therapeuticagent. Thus, the optical signal can be used to determine an amount ofradioactive therapeutic agent that has been delivered.

Another suitable sensor 970 for sensing an amount of therapeutic agentdelivered to a patient may include an electrical charge sensor. Asdiscussed above, the therapeutic agents used with the iontophoresissystem 910 will suitably be ionic substances that are electricallycharged. The electrical charge sensor can be configured to provide asignal that represents a sensed electric charge that is related to adetectable concentration of the therapeutic agent. Thus, the signal fromthe electrical charge sensor can be used to determine an amount oftherapeutic agent that has been delivered.

The sensor 970 may also be used in combination with the controller 948and an auxiliary device (not shown) to maintain certain parameters inthe fluid reservoir 928. For example, when it is desirable to warm orcool the therapeutic agent in the reservoir 928 to a set pointtemperature prior to administration, the controller can receive atemperature signal from the sensor 970 representative of a temperatureof the therapeutic agent and use the signal to control a heater and/orchiller that is operatively connected to the fluid reservoir. Likewise,when it is desirable to maintain the therapeutic agent in the reservoir928 to a set point pH prior to administration, the controller canreceive a pH signal from the sensor 970 representative of a pH of thetherapeutic agent and use the signal to control a pH effector that isoperatively connected to the fluid reservoir. In certain embodiments,the controller 948 may be further configured to prevent the power supply926 from supplying current to the electrodes 916, 918 until thetherapeutic agent in the reservoir 928 reaches the desired parameter(s).

In some embodiments, the sensor 970 can detect proper mounting of thepatch 912 on the body portion B. For example, the sensor 970 may be acircuit detector configured to detect the presence of a completedcircuit between the active electrode 916 and the indifferent electrode918. The controller 948 can be configured to prevent the power supply926 from supplying current to the electrodes 916, 918 until a circuit isdetected. In some embodiments, the system 910 can be configured to ameasure a resistance or impedance between the active electrode 916 andthe indifferent electrode 918. The controller 948 may suitably beconfigured to prevent the power supply 926 from supplying current to theelectrodes 916, 918 until the sensor shows that the resistance betweenthe two electrodes is within a predetermined range that is associatedwith the electrical resistance of the body portion B.

Referring to FIG. 18, an acoustic system for delivering a topicaltherapeutic agent to a body portion B is generally indicated at 1010.The acoustic system 1010 includes an acoustic energy generator 1012 thatgenerates acoustic energy configured to enhance delivery of the topicaltherapeutic agent to the body portion B. The acoustic system 1010 issuitably configured to deliver the therapeutic agent to the body portionB using sonophoresis. In one or more embodiments, the acoustic energygenerator 1012 is configured to generate acoustic energy having afrequency of at least about 15 kHz. In other embodiments, the acousticenergy generator 1012 is configured to generate acoustic energy having afrequency of from about 3 kHz to about 10 MHz (e.g., from about 20 kHzto about 1 MHz). In still other embodiments, the acoustic energygenerator 1012 is configured to generate ultrasound energy. In theexample illustrated in FIG. 18, a glycerin gel G acts as an acousticcoupler for operatively coupling the acoustic energy generator 1012 tothe body portion B. The therapeutic agent is shown dispersed in the gelG to illustrate how the acoustic energy generator would be used inconventional sonophoresis. In use, the acoustic energy generator 1012generates acoustic energy that enhances the permeability of the bodyportion B, causes cavitation, and/or causes diffusion of the therapeuticagent into the body portion (e.g., skin). The acoustic energy,therefore, enhances the delivery of the therapeutic agent into the bodyportion. However, some of the glycerin gel G is not able to be absorbedinto the body portion B. As a result, some of the therapeutic agentremains suspended in the gel G and is not delivered to the patient.

To prevent a portion of the therapeutic agent from remaining suspendedin unabsorbed gel G, the therapeutic agent may be applied to the bodyportion B separately from the gel. For example, in one method of usingthe acoustic system 1010, the therapeutic agent is applied to the bodyportion B before applying the gel and before applying the acousticenergy. In another method of using the acoustic system 1010, thetherapeutic agent is applied to the body portion B after applying thegel and acoustic energy and removing the gel from the body portion. Thetherapeutic agent can be dissolved in a suitable topical solvent andapplied directly to the body portion B (e.g., skin).

In suitable embodiments, the topical application of the therapeuticagent is further enhanced using iontophoresis. For example, aniontophoresis system, such as one having any of the features of thesystems 10, 110, 210, 310, 410, 510, 610, 710, 810, 910 discussed above,can be used to deliver a therapeutic agent using enhanced iontophoresisbefore or after using the acoustic system 1010. Thus, the acousticsystem 1010 is used to increase permeability of the body portion and/orfurther drive a therapeutic agent that is administered to a body portionB using iontophoresis. Suitably, the acoustic system 1010 can be used asan auxiliary device in an iontophoresis system. Optionally, a controllerof the iontophoresis can control the sequencing of acoustic energy andiontophoresis to enhance delivery of a therapeutic agent to a patient.It will be understood that the acoustic system 1010 can also be usedwithout iontophoresis.

When applied directly to the body portion B, the penetration of thetherapeutic agent can be monitored. For example, when the therapeuticagent is applied to the body portion B before the acoustic energy, theuser can monitor the absorption of the solvent into the skin (e.g.,using the sensor 970 of the iontophoresis system 910) and refrain fromapplying acoustic energy until all of the solvent is determined to beabsorbed. After all of the solvent appears to be absorbed, the user canapply acoustic energy to the body portion at the location where thetherapeutic agent was applied to improve penetration. When the acousticenergy is applied to the body portion B before the therapeutic agent,the user can wipe away the acoustic coupling gel before applying thetherapeutic agent. This prevents the therapeutic agent from becomingsuspended in the gel. By applying the therapeutic agent after theacoustic energy has been applied, delivery is enhanced because thepermeability of the body portion is increased by the acoustic energy.

It is believed that applying the acoustic energy through the acousticcoupling gel G at a separate time from the therapeutic agent results inmore certainty about the dose of the therapeutic agent that is deliveredto the patient. As a result, the above described method ofadministration can be used with dose-dependent and/or expensivetherapeutic agents that are not well-suited for suspension in anacoustic coupling gel. Examples of suitable therapeutic agents for usewith the methods of administration described above include, for example,chemotherapy drugs, Arnica, Voltaren, Morphine, salicylic acid,narcotics, chemotherapeutic agents, antiviral agents, RNA/DNAtreatments, cannabidiol, etc.

In one application, a user sequences the use of acoustic energy and awrinkle reducing agent to target skin of a patient. For example, afterapplying acoustic energy to the skin to increase permeability, a usercan remove residual coupling gel from the target skin and apply water.Due to the increased porosity of the skin, the water deeply penetratesthe skin to decrease wrinkles in the target area. Suitably, the targetskin can be all or part of the face of a patient, which can be submersedin a water bath after application of acoustic energy. In certainembodiments, additional wrinkle reducing agent can be suspended in theacoustic coupling gel to be administered to the patient during theapplication of acoustic energy. As an alternative to applying water in apost-acoustic-treatment administration, water can be applied to thetarget skin before applying the acoustic energy. At least some of thepre-applied water enters the pores of the target skin. Then, whenacoustic energy is applied to the target skin, it drives the retainedwater deeper into the skin to reduce wrinkles. In some wrinkle treatmentapplications, water can be supplemented or replaced with another wrinklereducing agent such as, for example, a collagen, a cream, an enhancer,etc. It is also contemplated that water could be replaced orsupplemented with Botox, for example, in a DMSO solution.

In another application, a user sequences the use of acoustic energy anda therapeutic agent for the treatment of psoriasis. A suitabletherapeutic agent is applied directly (e.g., without interference froman acoustic coupling gel) to the body part that suffers from psoriaticlesions in alternating fashion with acoustic energy (e.g., before orafter applying the acoustic energy). In one or more embodiments, thepsoriatic therapeutic agent is at least one of water, a chemotherapeuticagent, an RNA/DNA treatment, etc. By sequencing the application ofacoustic energy and therapeutic agent, psoriatic treatments can bedelivered topically, without an IV.

Basal cell cancers or other cancers such as melanoma could also betreated using these sequencing techniques. A suitable therapeutic agentfor treating cancer, such as a chemotherapy drug, is applied directly tothe body part where the cancer is located in alternating fashion withacoustic energy.

In still another application, a user can apply a surgical marker totarget tissue using the sequencing technique. A suitable surgical markeris applied directly to the body part that includes the target tissue inan alternating fashion with acoustic energy. A surgeon can subsequentlyuse the marker to identify tissue for, for example, resection.

In another application, a user can sequence acoustic energy with atherapeutic agent to treat Dupuytren's contracture. For example, atherapeutic agent such as Collagenous is applied to the affected skin inalternating fashion with acoustic energy. Since Collagenous is veryexpensive, it can be applied to the bare skin for, for example fromabout 30 seconds to about 5 minutes to ensure administration of acomplete dose.

In yet another application, a user can sequence acoustic energy withnegative pressure wound treatment to treat a wound, such as a diabeticulcer or other chronic wound. For example, a therapeutic agent may becombined with negative pressure therapy in alternating fashion withacoustic energy. In one or more embodiments, the negative pressuretherapy and therapeutic agent are combined using the iontophoresissystem 410 as discussed above and applied in alternating fashion withthe acoustic energy from the acoustic energy generator 1010.

In certain applications, a user can sequence focused acoustic energy ona specific location of skin to generate localized permeability thatallows a therapeutic agent to pass transdermally through the skin andinto a bodily lumen or organ. For example, a therapeutic agent can beapplied to the targeted area of the skin above a blood vessel inalternating fashion with focused acoustic energy to deliver thetherapeutic agent to the blood stream without an injection.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

When introducing elements of the present invention or the preferredembodiment(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above constructions withoutdeparting from the scope of the invention, it is intended that allmatter contained in the above description and shown in the accompanyingdrawings shall be interpreted as illustrative and not in a limitingsense.

What is claimed is:
 1. An iontophoresis system for delivering atherapeutic agent to a subject, the iontophoresis system comprising: aflexible patch support configured to be positioned over a wound on abody portion of a subject and create an airtight seal; an activeelectrode and an indifferent electrode configured to be connected to thesupport and configured to be in electrical communication with oneanother through the body portion of the subject, the active electrodeconfigured to be selectively coupled to a power supply to generate acurrent extending through the body portion between the active electrodeand the indifferent electrode; a controller configured to be operativelyconnected to the active electrode and the power supply to control anamount of power transmitted from the power supply to the activeelectrode to generate the current through the body portion; a vacuumsource operatively connected to an air fitting configured to extendthrough the flexible patch support, wherein the vacuum source isconfigured to apply a negative pressure between the flexible patchsupport and the wound on the body portion of the subject; a fluidreservoir preloaded with a therapeutic agent and configured to beconnected to the support in operative alignment with the activeelectrode for delivering the therapeutic agent from an outlet of thefluid reservoir into the body portion of the subject using anelectromotive force of the current passing through the body portion; anda removable cover covering at least the outlet of the reservoir tocontain the therapeutic agent within the fluid reservoir until the coveris removed from the outlet, wherein the wound on the body portion of thesubject is at least one of a diabetic ulcer and a chronic wound.
 2. Aniontophoresis system as set forth in claim 1, further comprising asensor coupled to the controller, the sensor configured to measure asufficient negative pressure between the flexible patch support and thewound on the body portion of the subject, and the controller configuredto activate the power supply to transmit power to the active electrodewhen the negative pressure measured by the sensor reaches apredetermined threshold.
 3. An iontophoresis system as set forth inclaim 2, wherein the cover comprises a peel strip extending over thedistal end of the support.
 4. An iontophoresis system as set forth inclaim 1, further comprising: a reusable module including the support;and a disposable module including the reservoir and the cover, thedisposable module being configured to be selectively connected to thereusable module.
 5. An iontophoresis system as set forth in claim 4,wherein at least one of the reusable module and the disposable modulecomprises a mounting structure for mounting said one of the reusablemodule and the disposable module on the other of the reusable module andthe disposable module.
 6. An iontophoresis system as set forth in claim4, wherein the disposable module includes the active electrode.
 7. Aniontophoresis system as set forth in claim 4, wherein the reusablemodule includes the indifferent electrode.
 8. An iontophoresis system asset forth in claim 7, wherein the reusable module includes the activeelectrode.
 9. An iontophoresis system as set forth in claim 1, whereinthe reservoir and the active electrode are each fastened to the support,the iontophoresis system further comprising a removable release stripseparating the reservoir and the active electrode.
 10. An iontophoresissystem as set forth in claim 1, wherein the reservoir comprises anabsorbent structure impregnated with the therapeutic agent.
 11. Aniontophoresis system as set forth in claim 10, wherein the absorbentstructure defines one or more passages configured for directing thetherapeutic agent toward the body portion through capillary flow.
 12. Aniontophoresis system as set forth in claim 1, further comprising systemelectronics coupled to the controller, the system electronics configuredto measure an impedance of the body portion of the subject, and thecontroller configured to activate the power supply to transmit power tothe active electrode when the impedance of the body portion reaches apredetermined threshold.
 13. An iontophoresis system as set forth inclaim 1, further comprising a mount configured to mount the support onthe body portion of the subject such that the therapeutic agentreservoir connected to the support is operatively connected to the bodyportion for delivering the therapeutic agent into the body portion. 14.An iontophoresis system as set forth in claim 1, wherein the controlleris configured to prevent the active electrode from drawing power fromthe power supply after a predetermined amount of time.
 15. Aniontophoresis system as set forth in claim 1, further comprising anauxiliary device configured to generate an auxiliary input transmissibleto the body portion of the subject, the controller being operativelyconnected to the auxiliary device to control the auxiliary device. 16.An iontophoresis system as set forth in claim 15, wherein the auxiliarydevice comprises one of a heater, a chiller, a vibrator, a magneticfield generator, and an acoustic energy generator.
 17. An iontophoresissystem as set forth in claim 1, further comprising a tissue workingstructure connected to the reservoir and configured to work the tissueof the body portion by one of abrading, puncturing, cutting, andexfoliating the tissue.
 18. An iontophoresis system as set forth inclaim 1, further comprising a sensor configured to sense one or moreparameters of the therapeutic agent, the body portion of the subject,and a treatment being administered by the iontophoresis system and totransmit a signal representative of the sensed parameter to thecontroller.
 19. An iontophoresis system as set forth in claim 18,wherein the controller is configured to receive the signal and use thesignal to control the amount of power from the power supply transmittedto the active electrode.
 20. A method of delivering a therapeutic agentto a body portion of a subject, the method comprising: removing a coverof an iontophoresis system extending over an outlet of a reservoirpreloaded with a therapeutic agent; engaging, after said removing acover, the iontophoresis system with the body portion of the subject sothat the reservoir is operatively aligned with the body portion; andusing a controller to convey power from a power supply to an activeelectrode of the iontophoresis system to draw a current through the bodyportion of the subject and deliver the preloaded therapeutic agent fromthe reservoir through the outlet and into the body portion of thesubject using an electromotive force of the current, wherein the bodyportion of the subject is at least one of a diabetic ulcer and a chronicwound.